Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development, and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo short bursts of growth and rapid proliferation (J. Biol. Chem. 1992, 267,10931-10934, and Science 1987, 235, 442-447.
While it is normally a regulated process, many diseases (characterized as angiogenic diseases) are driven by persistent, unregulated angiogenesis. Ocular neovascularization has been implicated as the most common cause of blindness and is responsible for approximately twenty different eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. The growth and metastasis of solid tumors are also dependent on angiogenesis (Cancer Res. 1986, 46, 467-473, and J. Natl. Cancer Inst. 1989, 82, 4-6). It has been shown that solid tumors cannot grow beyond 1 to 2 cubic millimeters without inducing the formation of new blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as the liver, the lungs, or the bones (N. Engl. J. Med. 1991, 324, 1-8).
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases, but there are disadvantages associated with these compounds. Fumagillin, a compound secreted by the fungus Aspergillus fumigatis fresenius, has demonstrated angioinhibitory effects, but has not been developed clinically due to the dramatic weight loss suffered by laboratory animals after prolonged exposure. TNP-470, a synthetic analog of fumagillin, also inhibits endothelial growth, but has been shown to induce asthenial and neurocortical toxicity in humans, limiting allowable dosages (J. Clin. Oncology 1999, 17, 2541).
As shown by these examples, there is still a need for compounds useful in treating angiogenic diseases which have improved profiles of activity. More specifically, there is a need for angiogenesis inhibitors which are safe for therapeutic use and which exhibit selective toxicity with respect to the pathological condition such as by selectively inhibiting the proliferation of endothelial cells while exhibiting no or a low degree of toxicity to normal (i.e. non-cancerous) cells. Such compounds should also be easily and cost-effectively made.